tbuckley/cabot-search huggingface dataset:
Real‐world Big‐data: Strengths and weaknesses of <scp>ASCO</scp>'s <scp>CancerLinQ</scp>® discovery multiple myeloma dataset
Authors: Christin B. DeStefano, Jennifer A. Thornton, Steven J. Gibson, Kevin Pham, Robert S. Miller, Kevin Sunderland
Journal: American Journal of Hematology (2023)

None of the authors have any financial or non-financial conflicts of interest to disclose. The opinions and assertions expressed herein are those of the authors and do not necessarily reflect the official policy or position of the US Air Force or the Department of Defense. None
Ad26.COV2.S and SARS-CoV-2 spike protein ferritin nanoparticle vaccine protect against SARS-CoV-2 Omicron BA.5 challenge in macaques
Authors: Jingyou Yu, Paul V Thomas, Michaela Sciacca, Cindy Wu, Jinyan Liu, Xuan He, Jessica Miller, Nicole P Hachmann, Nehalee Surve, Katherine McMahan, Catherine Jacob-Dolan, Olivia Powers, Kevin Hall, Julia Barrett, David Hope, Camille R Mazurek, Tetyana Murdza, William C Chang, Emily Golub, Phyllis A Rees, Caroline E Peterson, Agnes Hajduczki, Wei-Hung Chen, Elizabeth J Martinez, Elizabeth Hussin, Camille Lange, Hua Gong, Gary R Matyas, Mangala Rao, Mehul Suthar, Mona Boursiquot, Anthony Cook, Laurent Pessaint, Mark G Lewis, Hanne Andersen, Diane L Bolton, Nelson L Michael, M Gordon Joyce, Kayvon Modjarrad, Dan H Barouch
Journal: Cell Reports Medicine (2023)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines demonstrate reduced protection against acquisition of BA.5 subvariant but are still effective against severe disease. However, immune correlates of protection against BA.5 remain unknown. We report the immunogenicity and protective efficacy of vaccine regimens consisting of the vector-based Ad26.COV2.S vaccine and the adjuvanted spike ferritin nanoparticle (SpFN) vaccine against a high-dose, mismatched Omicron BA.5 challenge in macaques. The SpFNx3 and Ad26 + SpFNx2 regimens elicit higher antibody responses than Ad26x3, whereas the Ad26 + SpFNx2 and Ad26x3 regimens induce higher CD8 T cell responses than SpFNx3. The Ad26 + SpFNx2 regimen elicits the highest CD4 T cell responses. All three regimens suppress peak and day 4 viral loads in the respiratory tract, which correlate with both humoral and cellular immune responses. This study demonstrates that both homologous and heterologous regimens involving Ad26.COV2.S and SpFN vaccines provide robust protection against a mismatched BA.5 challenge in macaques.
Robust SARS-CoV-2 T cell responses with common TCRαβ motifs toward COVID-19 vaccines in patients with hematological malignancy impacting B cells
Authors: Thi H.O. Nguyen, Louise C. Rowntree, Lilith F. Allen, Brendon Y. Chua, Lukasz Kedzierski, Chhay Lim, Masa Lasica, G. Surekha Tennakoon, Natalie R. Saunders, Megan Crane, Lynette Chee, John F. Seymour, Mary Ann Anderson, Ashley Whitechurch, E. Bridie Clemens, Wuji Zhang, So Young Chang, Jennifer R. Habel, Xiaoxiao Jia, Hayley A. McQuilten, Anastasia A. Minervina, Mikhail V. Pogorelyy, Priyanka Chaurasia, Jan Petersen, Tejas Menon, Luca Hensen, Jessica A. Neil, Francesca L. Mordant, Hyon-Xhi Tan, Aira F. Cabug, Adam K. Wheatley, Stephen J. Kent, Kanta Subbarao, Theo Karapanagiotidis, Han Huang, Lynn K. Vo, Natalie L. Cain, Suellen Nicholson, Florian Krammer, Grace Gibney, Fiona James, Janine M. Trevillyan, Jason A. Trubiano, Jeni Mitchell, Britt Christensen, Katherine A. Bond, Deborah A. Williamson, Jamie Rossjohn, Jeremy Chase Crawford, Paul G. Thomas, Karin A. Thursky, Monica A. Slavin, Constantine S. Tam, Benjamin W. Teh, Katherine Kedzierska
Journal: Cell Reports Medicine (2023)

Immunocompromised hematology patients are vulnerable to severe COVID-19 and respond poorly to vaccination. Relative deficits in immunity are, however, unclear, especially after 3 vaccine doses. We evaluated immune responses in hematology patients across three COVID-19 vaccination doses. Seropositivity was low after a first dose of BNT162b2 and ChAdOx1 (∼26%), increased to 59%-75% after a second dose, and increased to 85% after a third dose. While prototypical antibody-secreting cells (ASCs) and T follicular helper (Tfh) cell responses were elicited in healthy participants, hematology patients showed prolonged ASCs and skewed Tfh2/17 responses. Importantly, vaccine-induced expansions of spike-specific and peptide-HLA tetramer-specific CD4+/CD8+ T cells, together with their T cell receptor (TCR) repertoires, were robust in hematology patients, irrespective of B cell numbers, and comparable to healthy participants. Vaccinated patients with breakthrough infections developed higher antibody responses, while T cell responses were comparable to healthy groups. COVID-19 vaccination induces robust T cell immunity in hematology patients of varying diseases and treatments irrespective of B cell numbers and antibody response.
The Role of Carbamoyl Phosphate Synthetase 1 as a Prognostic Biomarker in Patients With Acetaminophen-induced Acute Liver Failure
Authors: Raymond Kwan, Lu Chen, Min-Jung Park, Zemin Su, Sujith V.W. Weerasinghe, William M. Lee, Valerie L. Durkalski-Mauldin, Robert J. Fontana, M Bishr Omary
Journal: Clinical Gastroenterology and Hepatology (2023)
Chronic activation of Toll-like receptor 2 induces an ichthyotic skin phenotype
Authors: Hephzi Tagoe, Sakinah Hassan, Emily Bliss, Gehad Youssef, Wendy Heywood, Kevin Mills, John I Harper, Ryan F L O’Shaughnessy
Journal: British Journal of Dermatology (2023)

Ichthyosis defines a group of chronic conditions that manifest phenotypically as a thick layer of scales, often affecting the entire skin. While the gene mutations that lead to ichthyosis are well documented, the actual signalling mechanisms that lead to scaling are poorly characterized; however, recent publications suggest that common mechanisms are active in ichthyotic tissue and in analogous models of ichthyosis.To determine common mechanisms of hyperkeratosis that may be easily targeted with small-molecule inhibitors.We combined gene expression analysis of gene-specific short hairpin RNA (shRNA) knockdowns in rat epidermal keratinocytes (REKs) of two genes mutated in autosomal recessive congenital ichthyosis (ARCI), Tgm1 and Alox12b, and proteomic analysis of skin scale from patients with ARCI, as well as RNA sequencing data from rat epidermal keratinocytes treated with the Toll-like receptor 2 (TLR2) agonist Pam3CSK4.We identified common activation of the TLR2 pathway. Exogenous TLR2 activation led to increased expression of important cornified envelope genes and, in organotypic culture, caused hyperkeratosis. Conversely, blockade of TLR2 signalling in keratinocytes from patients with ichthyosis and our shRNA models reduced the expression of keratin 1, a structural protein overexpressed in ichthyosis scale. A time course of TLR2 activation in REKs revealed that although there was rapid initial activation of innate immune pathways, this was rapidly superseded by widespread upregulation of epidermal differentiation-related proteins. Both nuclear factor kappa B phosphorylation and GATA3 upregulation was associated with this switch, and GATA3 overexpression was sufficient to increase keratin 1 expression.Taken together, these data define a dual role for TLR2 activation during epidermal barrier repair that may be a useful therapeutic modality in treating diseases of epidermal barrier dysfunction.
VMP1 prevents Ca2+ overload in endoplasmic reticulum and maintains naive T cell survival
Authors: Ying Liu, Yuying Ma, Jing Xu, Guangyue Zhang, Xiaocui Zhao, Zihao He, Lixia Wang, Na Yin, Min Peng
Journal: The Journal of Experimental Medicine (2023)

Ca2+ in endoplasmic reticulum (ER) dictates T cell activation, proliferation, and function via store-operated Ca2+ entry. How naive T cells maintain an appropriate level of Ca2+ in ER remains poorly understood. Here, we show that the ER transmembrane protein VMP1 is essential for maintaining ER Ca2+ homeostasis in naive T cells. VMP1 promotes Ca2+ release from ER under steady state, and its deficiency leads to ER Ca2+ overload, ER stress, and secondary Ca2+ overload in mitochondria, resulting in massive apoptosis of naive T cells and defective T cell response. Aspartic acid 272 (D272) of VMP1 is critical for its ER Ca2+ releasing activity, and a knockin mouse strain with D272 mutated to asparagine (D272N) demonstrates all functions of VMP1 in T cells in vivo depend on its regulation of ER Ca2+. These data uncover an indispensable role of VMP1 in preventing ER Ca2+ overload and maintaining naive T cell survival.
Strong Positive Selection in<i>Aedes aegypti</i>and the Rapid Evolution of Insecticide Resistance
Authors: R Rebecca Love, Josh R Sikder, Rafael J Vivero, Daniel R Matute, Daniel R Schrider
Journal: Molecular Biology and Evolution (2023)

Aedes aegypti vectors the pathogens that cause dengue, yellow fever, Zika virus, and chikungunya and is a serious threat to public health in tropical regions. Decades of work has illuminated many aspects of Ae. aegypti's biology and global population structure and has identified insecticide resistance genes; however, the size and repetitive nature of the Ae. aegypti genome have limited our ability to detect positive selection in this mosquito. Combining new whole genome sequences from Colombia with publicly available data from Africa and the Americas, we identify multiple strong candidate selective sweeps in Ae. aegypti, many of which overlap genes linked to or implicated in insecticide resistance. We examine the voltage-gated sodium channel gene in three American cohorts and find evidence for successive selective sweeps in Colombia. The most recent sweep encompasses an intermediate-frequency haplotype containing four candidate insecticide resistance mutations that are in near-perfect linkage disequilibrium with one another in the Colombian sample. We hypothesize that this haplotype may continue to rapidly increase in frequency and perhaps spread geographically in the coming years. These results extend our knowledge of how insecticide resistance has evolved in this species and add to a growing body of evidence suggesting that Ae. aegypti has an extensive genomic capacity to rapidly adapt to insecticide-based vector control.
Association of Preoperative Medical Consultation With Reduction in Adverse Postoperative Outcomes and Use of Processes of Care Among Residents of Ontario, Canada
Authors: Weiwei Beckerleg, Daniel Kobewka, Duminda N. Wijeysundera, Manish M. Sood, Daniel I. McIsaac
Journal: JAMA Internal Medicine (2023)

It is uncertain whether preoperative medical consultation reduces adverse postoperative clinical outcomes.
ATM inhibition enhances the efficacy of radiation across distinct molecular subgroups of pediatric high-grade glioma
Authors: Jia Xie, Teneema Kuriakose, Brandon Bianski, Nathaniel Twarog, Evan Savage, Ke Xu, Xiaoyan Zhu, Chen He, Baranda Hansen, Hong Wang, Anthony High, Yuxin Li, Jerold E Rehg, Heather S Tillman, Burgess B Freeman, Zoran Rankovic, Arzu Onar-Thomas, Yiping Fan, Gang Wu, Junmin Peng, Shondra Miller, Suzanne J Baker, Anang A Shelat, Christopher L Tinkle
Journal: Neuro-Oncology (2023)

Abstract Background Pediatric high-grade glioma (pHGG) is largely incurable and accounts for most brain tumor-related deaths in children. Radiation is a standard therapy, yet the benefit from this treatment modality is transient, and most children succumb to disease within 2 years. Recent large-scale genomic studies suggest that pHGG has alterations in DNA damage response (DDR) pathways that induce resistance to DNA damaging agents. The aim of this study was to evaluate the therapeutic potential and molecular consequences of combining radiation with selective DDR inhibition in pHGG. Methods We conducted an unbiased screen in pHGG cells that combined radiation with clinical candidates targeting the DDR and identified the ATM inhibitor AZD1390. Subsequently, we profiled AZD1390 + radiation in an extensive panel of early passage pHGG cell lines, mechanistically characterized response to the combination in vitro in sensitive and resistant cells and evaluated the combination in vivo using TP53 wild-type and TP53 mutant orthotopic xenografts. Results AZD1390 significantly potentiated radiation across molecular subgroups of pHGG by increasing mutagenic nonhomologous end joining and augmenting genomic instability. In contrast to previous reports, ATM inhibition significantly improved the efficacy of radiation in both TP53 wild-type and TP53 mutant isogenic cell lines and distinct orthotopic xenograft models. Furthermore, we identified a novel mechanism of resistance to AZD1390 + radiation that was marked by an attenuated ATM pathway response which dampened sensitivity to ATM inhibition and induced synthetic lethality with ATR inhibition. Conclusions Our study supports the clinical evaluation of AZD1390 in combination with radiation in pediatric patients with HGG.
DrosOmics: A Browser to Explore -omics Variation Across High-Quality Reference Genomes From Natural Populations of<i>Drosophila melanogaster</i>
Authors: Marta Coronado-Zamora, Judit Salces-Ortiz, Josefa González
Journal: Molecular Biology and Evolution (2023)

Abstract The advent of long-read sequencing technologies has allowed the generation of multiple high-quality de novo genome assemblies for multiple species, including well-known model species such as Drosophila melanogaster. Genome assemblies for multiple individuals of the same species are key to discover the genetic diversity present in natural populations, especially the one generated by transposable elements, the most common type of structural variant. Despite the availability of multiple genomic data sets for D. melanogaster populations, we lack an efficient visual tool to display different genome assemblies simultaneously. In this work, we present DrosOmics, a population genomic-oriented browser currently containing 52 high-quality reference genomes of D. melanogaster, including annotations from a highly reliable set of transposable elements, and functional transcriptomics and epigenomics data for 26 genomes. DrosOmics is based on JBrowse 2, a highly scalable platform, which allows the visualization of multiple assemblies at once, key to unraveling structural and functional features of D. melanogaster natural populations. DrosOmics is an open access browser and is freely available at http://gonzalezlab.eu/drosomics.
Preoperative Medical Consultation—Time to Reevaluate a Questionable Process
Authors: Mutya Mithi Del Rosario, Rita F. Redberg, Deborah Grady
Journal: JAMA Internal Medicine (2023)

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Ancient and Nonuniform Loss of Olfactory Receptor Expression Renders the Shark Nose a De Facto Vomeronasal Organ
Authors: Adnan S Syed, Kanika Sharma, Maxime Policarpo, Sara Ferrando, Didier Casane, Sigrun I Korsching
Journal: Molecular Biology and Evolution (2023)

Cartilaginous fishes are renowned for a keen sense of smell, a reputation based on behavioral observations and supported by the presence of large and morphologically complex olfactory organs. At the molecular level, genes belonging to the four families coding for most olfactory chemosensory receptors in other vertebrates have been identified in a chimera and a shark, but it was unknown whether they actually code for olfactory receptors in these species. Here, we describe the evolutionary dynamics of these gene families in cartilaginous fishes using genomes of a chimera, a skate, a sawfish, and eight sharks. The number of putative OR, TAAR, and V1R/ORA receptors is very low and stable, whereas the number of putative V2R/OlfC receptors is higher and much more dynamic. In the catshark Scyliorhinus canicula, we show that many V2R/OlfC receptors are expressed in the olfactory epithelium in the sparsely distributed pattern characteristic for olfactory receptors. In contrast, the other three vertebrate olfactory receptor families are either not expressed (OR) or only represented with a single receptor (V1R/ORA and TAAR). The complete overlap of markers of microvillous olfactory sensory neurons with pan-neuronal marker HuC in the olfactory organ suggests the same cell-type specificity of V2R/OlfC expression as for bony fishes, that is, in microvillous neurons. The relatively low number of olfactory receptors in cartilaginous fishes compared with bony fishes could be the result of an ancient and constant selection in favor of a high olfactory sensitivity at the expense of a high discrimination capability.
Efficacy and safety of topical brepocitinib cream for mild-to-moderate chronic plaque psoriasis: a phase IIb randomized double-blind vehicle-controlled parallel-group study
Authors: Megan N Landis, Stacy R Smith, Gabriel Berstein, Gerald Fetterly, Pranab Ghosh, Gang Feng, Vivek Pradhan, Sudeepta Aggarwal, Christopher Banfield, Elena Peeva, Michael S Vincent, Jean S Beebe, Sanela Tarabar
Journal: British Journal of Dermatology (2023)

Plaque psoriasis (PsO) is an inflammatory skin disease driven, in part, by the activation of Janus kinase (JAK) signalling pathways.To assess the efficacy and safety of multiple doses of topical brepocitinib, a tyrosine kinase 2/JAK1 inhibitor, in participants with mild-to-moderate PsO.This phase IIb multicentre randomized double-blind study was conducted in two stages. In stage 1, participants received one of eight treatments for 12 weeks: brepocitinib 0.1% once daily, 0.3% once or twice daily, 1.0% once or twice daily, 3.0% once daily, or vehicle once or twice daily. In stage 2, participants received brepocitinib 3.0% twice daily or vehicle twice daily. The primary endpoint was the change from baseline in Psoriasis Area and Severity Index (PASI) score at week 12, analysed using analysis of covariance. The key secondary endpoint was the proportion of participants who achieved a Physician Global Assessment response [score of clear (0) or almost clear (1) and an improvement of ≥ 2 points from baseline] at week 12. Additional secondary endpoints included the difference vs. vehicle in change from baseline in PASI, using mixed-model repeated measures, and the change from baseline in Peak Pruritus Numerical Rating Scale at week 12. Safety was monitored.Overall, 344 participants were randomized. Topical brepocitinib did not result in statistically significant changes compared with respective vehicle controls in the primary or key secondary efficacy endpoints for any dose group. At week 12, least squares mean change from baseline in PASI score ranged from -1.4 to -2.4 for the brepocitinib once-daily groups vs. -1.6 for vehicle once daily, and from -2.5 to -3.0 for the brepocitinib twice-daily groups vs. -2.2 for vehicle twice daily. From week 8, change from baseline in PASI score separated from vehicle in all brepocitinib twice daily groups. Brepocitinib was well tolerated, with adverse events (AEs) occurring at similar rates across groups. One participant in the brepocitinib 1.0% once-daily group developed a treatment-related AE of herpes zoster in the neck area.Topical brepocitinib was well tolerated but did not result in statistically significant changes compared with vehicle when administered at the doses evaluated to treat signs and symptoms of mild-to-moderate PsO.
Diagnosis and treatment outcomes from prebronchodilator spirometry performed alongside lung cancer screening in a Lung Health Check programme
Authors: Claire Bradley, Alison Boland, Louisa Clarke, Naomi Dallinson, Claire Eckert, Deborah Ellames, Jonathan Finn, Rhian Gabe, Neil Hancock, Martyn PT Kennedy, Jason Lindop, Ayad Mohamed, Gabriel Mullen, Rachael L Murray, Suzanne Rogerson, Bethany Shinkins, Irene Simmonds, Sara Upperton, Anne Wilkinson, Philip A Crosbie, Matthew EJ Callister
Journal: Thorax (2023)

Introduction Incorporating spirometry into low-dose CT (LDCT) screening for lung cancer may help identify people with undiagnosed chronic obstructive pulmonary disease (COPD), although the downstream impacts are not well described. Methods Participants attending a Lung Health Check (LHC) as part of the Yorkshire Lung Screening Trial were offered spirometry alongside LDCT screening. Results were communicated to the general practitioner (GP), and those with unexplained symptomatic airflow obstruction (AO) fulfilling agreed criteria were referred to the Leeds Community Respiratory Team (CRT) for assessment and treatment. Primary care records were reviewed to determine changes to diagnostic coding and pharmacotherapy. Results Of 2391 LHC participants undergoing prebronchodilator spirometry, 201 (8.4%) fulfilled the CRT referral criteria of which 151 were invited for further assessment. Ninety seven participants were subsequently reviewed by the CRT, 46 declined assessment and 8 had already been seen by their GP at the time of CRT contact. Overall 70 participants had postbronchodilator spirometry checked, of whom 20 (29%) did not have AO. Considering the whole cohort referred to the CRT (but excluding those without AO postbronchodilation), 59 had a new GP COPD code, 56 commenced new pharmacotherapy and 5 were underwent pulmonary rehabilitation (comprising 2.5%, 2.3% and 0.2% of the 2391 participants undergoing LHC spirometry). Conclusions Delivering spirometry alongside lung cancer screening may facilitate earlier diagnosis of COPD. However, this study highlights the importance of confirming AO by postbronchodilator spirometry prior to diagnosing and treating patients with COPD and illustrates some downstream challenges in acting on spirometry collected during an LHC.